Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (NSAIDs)

a technology of anti-inflammatory drugs and compositions, which is applied in the direction of drug compositions, peptide/protein ingredients, and elcosanoid active ingredients, etc., can solve the problems of toxic and undesired high drug levels, lack of patient compliance, and inability to adjust dosage, so as to achieve the effect of keeping the production cost at a low level

Inactive Publication Date: 2003-07-29
TAKEDA PHARMA AS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

When a coating is present on the multiple-units of the first fraction then it could advantageous be of the same kind as an outer coating on the multiple-units of the second fraction. The employment of the same kind of coating for each fraction may be performed with substantially identical procedures and materials and the production cost can be kept at a low level.

Problems solved by technology

However, it is not a suitable approach to increase dosage as such doses may produce toxic and undesired high drug levels.
This approach is generally associated with several potential problems, such as a large peak (toxic effect) and valley (non-active drug level) effect, and a lack of patient compliance leading to drug therapy inefficiency or failure.
If, however, the plasma concentration is kept constant over the therapeutic level using conventional tablets, an unacceptably high daily dosage is required if the active substance is not administered very frequently.
Especially in those cases where the drug substance has a low solubility in an acidic medium having a pH of from about 1 to about 3, i.e. a pH corresponding to the pH in the stomach, the traditional formulation approach will lead to a pharmaceutical composition which has a suitable fast disintegration time but not necessarily a suitable dissolution rate of the drug substance under acidic conditions, i.e. a plain tablet will rapidly disintegrate into granules but the dissolution of the drug substance from the composition and / or the disintegrated composition under acidic conditions may be unsuitable low due to the solubility properties of the drug substance itself.
Moreover, patients suffering from pain and / or inflammatory conditions and / or related conditions very often require high daily dosages of NSAID substances.
Thus, a major disadvantage of the once-a-day treatment in the art may be a low plasma concentration at the end of the dosing period and thereby the lack of therapeutic response.
It is also important that an NSAID composition for daily administration comprises the active ingredient in such a way that the composition has a reliable dissolution rate since a change in the dissolution pattern of the NSAID substance could be disadvantageous for the patient.

Method used

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  • Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (NSAIDs)
  • Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (NSAIDs)
  • Modified release multiple-units compositions of non-steroid anti-inflammatory drug substances (NSAIDs)

Examples

Experimental program
Comparison scheme
Effect test

second embodiment

To ensure that the final composition has a proper constitution with respect to the weight amount of first fraction relative to the amount of second fraction, the in vitro dissolution characteristics of the first and second fractions are in one embodiment adapted so that the first fraction is substantially released when the release from the second fraction is initiated, corresponding to at least 50% w / w release of the first fraction at the time at the most about 15% w / w such as, e.g., at the most about 10% or at the most about 5% w / w of the second fraction is released, as measured by the dissolution method III described herein. In addition, the in vitro dissolution characteristics of the first and second fractions in the same or a second embodiment as mentioned above are adapted so that the first fraction is substantially released when the release from the second fraction is initiated, corresponding to at least 70% w / w release of the first fraction at the time at the most about 20% w...

example 1

Preparation of Cores Containing Lornoxicam and Coating of the Cores with a CR Coating

Batch Nos. 04029831 (uncoated pellet cores) and 05029833 (coated pellet cores) were prepared.

Lornoxicam pellet cores were prepared by manufacturing of pellet cores and subsequent coating with an inner and an outer coat.

The pellet cores were prepared by the use of an extrusion / spheronization technique.

The ingredients are listed in Table 1. The ingredients I and II were mixed in a beaker by stirring, wetted with 150 g water and then mixed to a homogenous mass. The ingredients III to VII were filled into a Moulinex laboratory size mixer and mixed for 5 min, whereafter the homogenous mass was added and mixed. The beaker was rinsed with the remaining water and added to the mixer.

The resulting mass was extruded in a Nica E 140 extruder with a screen size of 0.6 mm. The extrudate was spheronized in a laboratory size spheronizer at a rotation speed of 700 rpm for 4 min. The pellet cores thus produced were d...

example 2

Preparation of Pellet Cores According to the Invention Leaving Out a Surface Active Substance from the Cores

Batch No. 09029831 (uncoated pellet cores) was prepared.

Lornoxicam pellet cores were prepared by using the ingredients listed in Table 3.

The pellet cores were prepared by the use of the extrusion / spheronization technique as described in Example 1, wherein the ingredients I to IV were mixed for 5 min in a Moulinex laboratory size mixer, whereafter the ingredients V was added.

The release of lornoxicam from pellet cores was determined by dissolution method I (pH 7,4) and is as follows:

From the dissolution data given above it is seen that the release is not accomplished after 1 hour and compared with the result obtained with the uncoated pellet cores in Example 1 it seems as if the inclusion of a surface active agent like e.g. polysorbate 20 has a significant influence on the dissolution rate.

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Abstract

An oral pharmaceutical modified release multiple-units composition for the administration of a therapeutically and/or prophylactically effective amount of a non-steroid anti-inflammatory drug substance to obtain both a relatively fast onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time is disclosed.

Description

This application is a 371 of PCT / DK98 / 00388 filed Sep. 10 1998,The present invention relates to an oral pharmaceutical modified release multiple-units composition for the administration of a therapeutically and / or prophylactically effective amount of a non-steroid anti-inflammatory drug substance (in the following abbreviated "an NSAID substance") to obtain both a relatively fast or quick onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time. The modified release multiple-units composition comprises at least two fractions of multiple units such as a first and a second fraction. The first fraction comprises individual units which are designed to quickly release the drug substance and the second fraction comprises individual units which are designed to slowly release the drug substance to enable a delayed and extended release of the drug substance. Typically, the second fraction comprises multiple unit...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K45/00A61K9/20A61K9/50A61K45/06A61K31/542A61K9/16A61K9/00A61K9/52A61K9/54A61K31/122A61K31/18A61K31/192A61K31/196A61K31/216A61K31/34A61K31/381A61K31/40A61K31/405A61K31/407A61K31/4152A61K31/4164A61K31/4184A61K31/44A61K31/496A61K31/519A61K31/5415A61K31/557A61K31/60A61K31/704A61K38/00A61P29/00
CPCA61K9/2081A61K9/5084A61K31/542A61K45/06A61P25/00A61P29/00
Inventor SKINH.O SLASHED.J, ANNETTEBERTELSEN, POUL
Owner TAKEDA PHARMA AS
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